1. Field of the Invention
The present invention relates generally to the field of cancer therapy. More particularly, it concerns a method of inducing p53-mediated apoptosis in tumor cells by inhibiting DNA repair.
2. Description of Related Art
Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and the rate of cell death. Disruption of this balance is thought to be a major event in the development of cancer. The inhibition of apoptosis, or programmed cell death, has been linked to this disruptive event. The effects of cancer are catastrophic, causing over half a million deaths per year in the United States alone.
Though conventional therapies are available, development of resistance to such treatment is a major obstacle to treatment of cancer. For example, glioblastoma multiforme is the most common intracranial brain tumor and is particularly resistant to therapy, and rapidly becomes more resistant as therapy continues. Glioblastoma tumors are highly vascularized, infiltrate the brain extensively and can attain a very large size. Glioblastomas are unilaterally fatal and patients have a mean survival time of about one year from the time of diagnosis.
Traditional treatment modalities for glioblastoma include surgery, radiotherapy, and chemotherapy. However, glioblastomas respond poorly to most chemotherapeutic agents, even though the blood brain barrier is broken down as a consequence of the disease. Certain chemotherapeutic agents such as cisplatin, carmustine, procarbazine and 5-fluororacil are somewhat efficacious in the treatment of glioblastoma but the tumors are never completely eradicated by these methods. A major reason for the failure of traditional treatment therapies of glioblastoma is the development of resistance in subsets of tumor cells. One reason for this resistance appears to be a result of genetic changes that accompany disease progression, including loss of wild-type p53 function. Mutations in p53 occur in over 50% of adult glioblastoma cases and are associated more with disease progression.
The p53 gene is well recognized as a tumor suppressor gene (Montenarh, 1992). There is now considerable evidence linking mutations of p53 in the oncogenesis of many human cancers. There are numerous reports demonstrating that the growth of colon, glioblastoma, breast cancer, osteosarcoma and lung tumor cells can be suppressed by the expression of wild-type p53. The introduction of wild-type p53 into a wide variety of p53-mutated cells, using viral delivery methods, has resulted in the expression of the wild-type p53 transgene and a suppression of the malignant phenotype. These observations demonstrate that a high level of expression of wild-type p53 is a desirable course for the treatment of oncogenic malignancy.
More recently, p53 has been shown to be a trigger of apoptosis (Yonish-Rouacli et al., 1991; Shaw et al., 1992; Lowe et al., 1993; Lotem and Sachs, 1993; Clarke et al., 1993) which suggests that the disruption of p53 in tumors has significant consequences for cancer therapy. The desensitization of tumor cells to the effects of traditional cancer therapies as a result of p53 mutation may aid in the progression of disease. In addition to p53 mutations, cancer therapies such as radiotherapy and chemotherapy that induce DNA damage to a tumor cell contribute to the development of resistance of tumors. Several studies suggest that treatment of tumors with DNA damaging agents results in up-regulated DNA damage repair mechanisms, which could account for increased resistance to DNA damaging therapy. In normal cells, DNA damage results in cell cycle arrest and induction of DNA repair mechanisms, so as to prevent the transfer of damaged DNA to the next generation of cells. Cells that sustain high levels of DNA damage, such as tumor cells that exhibit high levels of karyotypic instability, or cells that are treated with DNA damaging agents, are induced to undergo apoptosis. This switch from either arrest and DNA repair or apoptosis is mediated by p53. These effects, among others, show that there remains a need for improved methods of cancer therapy.